cellular pathology prof orla sheils causes of disease adaptive responses 2nd year pathology 2011

Cellular PathologyProf Orla Sheils

Causes of Disease Adaptive Responses

2nd year Pathology 2011


References, Reading and Websites

Pathologic Basis of Disease - Robbins.

Cell, Tissue and Disease. The Basis of Pathology- Woolf

Pathology Secrets – Damjanov. Chapters 1 and 7

http://www.pathguy.com

http://medlib.med.utah.edu/WebPath/webpath.html

http://www.pathguy.com/

http://medlib.med.utah.edu/WebPath/webpath.html


http://www.medicine.tcd.ie/Histopathology/courses/studentarea.htm

Lecture available on line at:

http://www.tcd.ie/Histopathology/courses/studentarea.htm




Causes of DiseaseDisease does not exist except as a reaction to

injury.

Concept of Homeostasis. “The Steady State” or equilibrium with the environment.

Cellular adaptation.

Physiologic.

Morphologic.

At the limits of cellular adaptation or in cases where adaptation is not possible then “cell injury” may occur.


Cell injury

Reversible. Cell swelling/Hydropic change.

Fatty Change.

Irreversible.

Cell Death (Myocardial Infarction)


Types of Cell Injury

1) Oxygen Deprivation / Re-oxygenation • (Free radicals).

2) Physical Agents.

3) Chemical Agents / Drugs.

4) Infectious Agents.

5) Immunologic Reactions.

6) Genetic Derangements.

7) Nutritional Imbalances.

8) Aging (See next lecture)


Cell injuryExogenous:

Physical (Heat and cold) Chemical (toxins and drugs) Biological (Viruses and bacteria)

Endogenous: Genetic defects. Metabolites. Hormones. Cytokines


1) Oxygen DeprivationTerms: Hypoxia/Anoxia.

Ischaemia.

Hypoxia is a reduction of the amount of oxygen delivered to cells. It is the most common cause of cell injury and death.

Ischaemia is a reduction in the perfusion of a body part or organ in relation to its needs.


Hypoxia V Ischaemia.

Hypoxia affects aerobic oxidative respiration. Glycolytic energy production can continue but there is greatly diminished ATP supply.

Causes of hypoxia: Ischaemic hypoxia (Acute white limb, Heart Failure) Hypoxic hypoxia (Altitude, respiratory failure) Anaemic hypoxia (Anaemia) Histotoxic hypoxia (CO Poisoning, Cyanide)


CO poisoning- cherry pink skin discolouration


Hypoxia V Ischaemia.

Ischaemia compromises the availability of metabolic substrates. It is a form of hypoxia.

Causes of Ischaemia: Impeded arterial flow, impeded venous drainage.

Development of an infarct depends on: Anatomic pattern of vascular supply Rate of vascular occlusion Vunerablity of tissue affected Oxygen content of blood


Hypoxia Neurons: Frank necrosis after being deprived of

oxygen for 3-5 minutes at normal temperature clinically, brain damage follows much shorter intervals.

Heart muscle cells can last 30-60 minutes.

Liver cells and renal tubular cells can last for 1-2 hours without oxygen before they are irreversibly damaged ( but easy to replace.)

Skin fibroblasts can last for many hours.


2) Physical Agents.

Mechanical Trauma.

Extremes of Temperature.

Barotrauma.

Electric Shock.

Radiation.


Radiation Electromagnetic (Non-ionizing) radiation:

Long wavelengths, low frequency Radiowaves, microwaves Vibration and rotation of atoms

Particulate (Ionizing) radiation: Short wavelengths, high frequency X-rays, gamma rays, cosmic rays Ionize biologic molecules and eject electrons

UV injury- UVA/UVB/UVC: skin cancer

Radiation Dose is measured in rads (1 rad produces absorption of 100 ergs energy/gm tissue, 100 rads = 1 Gray).

Background Radiation = .00001Gy.


Effects of Radiation

Main target molecule = DNA

Early effects of radiation: Acute Radiation sickness.

0.5 - 2 Gy: Fatigue, Nausea, vomiting. 2 – 6 Gy: Haematopoietic radiation syndrome 3 – 10 Gy: GIT radiation syndrome. Diarrhea and fluid and

electrolyte loss. 50-100% Mortality within 2 weeks. Over 10 Gy: Cerebral radiation syndrome. RIP in 14-36 hrs. 1000 Gy: RIP Stat.


Late effects of radiation: Atrophy. Narrowing of blood vessels. Fibrosis. Inflammation Cataracts Carcinoma. Teratogenic.


3) Chemical Agents and Drugs

Hypertonic Solutions.

Oxygen.

Poisons: Arsenic, Cyanide, Mercury.

Environmental Pollutants.

Insecticides/ herbicides.

CO

Asbestos 1) Interstitial lung fibrosis. 2) Bronchogenic carcinoma. 3) Pleural Effusions. 4) Pleural plaques. 5) Mesotheliomas.

Recreational Drugs / C2H5OH


Chemical Injury

Biological molecules react like any other chemicals. Acids and alkalis hydrolyze membranes Poisons like mercuric ion tie up sulfhydryl groups and

destroy the cell. Formalin / formaldehyde crosslink amino groups on

proteins and nucleic acids. Histopathologists use this chemistry to “fix tissues”.

Current thinking is that most simple poisons that cause actual cell necrosis require activation to form free radicals. For example, carbon tetrachloride (old-fashioned cleaning fluid) is turned into CCl3

.- radical in the smooth endoplasmic reticulum of the liver.


Chemical Injury Other classic poisons affect the more vulnerable parts of

the cells.

Depending on the poison and dose, there may or may not be necrosis: Cell membranes: digitalis Oxidative phosphorylation: cyanide Ribosomes: toadstools Genes: chemotherapeutic agents Synapses: strychnine, ergot


4) Infectious Agents.Bacteria

Viruses

Fungi

Chlamydiae,Rickettsiae,Mycoplasma

Protozoa

Helminths

Ectoparasites

Bacteriophages, Plasmids

Prions.


How microrganisms cause disease

Entering cells

Releasing toxins

Damaging blood vessels

Inducing host responses with additional damage Suppuration Scarring Hypersensitivity reactions


Exotoxin Endotoxin

Secreted from living organism

Part of dead organism

Protein LPS

Elicits immune reaction No immune reaction (weak)

Heat labile Heat stable


Toxin Producing OrganismsVibrio cholera.

Activation of cAMP. Massive secretory diarrhoea.

Diphtheria. Inactivates ribosomes. Damage to heart, nerves, liver, kidneys.

Clostridia perfringens/botulinum/tetaniDegrade cell membranes: gangreneBlock ACh release: botulism/tetanus

Staph. aureus.Scalded skin syndrome


5) Immunologic Hypersensitivity

Exaggerated response of immune system to exogenous antigens.

AutoimmunityInappropriate response of immune system to

endogenous antigens.


6) Genetic Derangements

Chromosomal abnormalities.

Single gene disorders.


7) Nutritional Imbalances. Protein energy deficiency (PEM)

Marasmas. Muscle wasting, wrinkled skin, Hair loss. Kwashiorkor. Excess protein deficiency: Scaly skin, Swollen

abdomen (ascites), swollen ankles, Hypoalbuminemia.

Specific vitamin deficiencies Vit C: (ascorbic acid) Vit. D: Rickets, Osteomalacia. Vit A: Xeropthalmia, Bitot’s spots, keratomalacia, night blindness Niacin: Pellagra- Dermatitis, Diarrhoea, Dementia

Anorexia nervosa.

Dietary indiscretion – Cholesterol.


Cellular adaptionHyperplasia.

Hypertrophy.

Atrophy.

Metaplasia.

If cell cannot adapt to injury/stress, it may undergo apoptosis (programmed cell death).

If this does not occur, the cell will undergo necrosis.


Hyperplasia

An increase in the Number of cells in an organ or tissue.

Hyperplasia means cells growing more numerous.

Usually accompanied by hypertrophy.

Can only occur in cells capable of making new DNA (capable of division).


Physiologic Hyperplasia

A Demand - led physiological event

Hormonal: Endometrial proliferation after oestrogen stimulation.

Compensatory: Hyperplasia of liver after partial hepatectomy.

Breast and Thyroid at times of puberty and pregnancy


Pathologic Hyperplasia

Hyperoestrogenism and atypical endometrial hyperplasia.

Squamous hyperplasia induced by viruses. HPV (wart) virus.


Endometrial hyperplasia


Benign Prostatic Hyperplasia

MicroscopyMacroscopy


HypertrophyHYPERTROPHY: Increase in the sizes of

cells, and hence the size of the organ.

Often occurs in cells that have limited abilities to divide e.g. muscle

Physiological: Skeletal muscle hypertrophy due to exercise

Pathological: Hypertrophy of the overworked heart of an aerobic athlete, hypertension victim, or victim of aortic valve stenosis or other cardiac structural defect


Hypertrophy


Left Ventricular Hypertrophy


Atrophy

ATROPHY: "Shrinkage in the size of the cell by loss of cell substance" (Robbins), without the cell actually dying. When many cells each become smaller, the organ itself become smaller. Defined this way, atrophy is very reversible.


Causes of Atrophy

Disuse Atrophy - Workload.

Denervation atrophy.

blood supply.

Inadequate nutrition.

Loss of endocrine stimulation.

Senile atrophy.

Pressure/Involution.


Muscle Atrophy


Cerebral atrophy


Metaplasia

METAPLASIA: (Adaptive) substitution of one type of adult or fully differentiated cell for another type of adult (or fully differentiated) cell. -Robbins.

"A reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type." -Robbins.

"Conversion of a differentiated cell type into another" -- R&F.


Metaplasia


MetaplasiaTransformation of the gallbladder or urinary

bladder epithelium to stratified squamous epithelium in the presence of foreign bodies (stones, schistosome eggs)

Replacement of airway pseudostratified mucin-producing ciliated columnar epithelium by an epithelium consisting almost entirely of goblet cells (cigarette smokers and asthmatics)

Replacement of the columnar mucoid epithelium of the endocervix by stratified squamous epithelium in women infected with wart virus


Metaplasia

Replacement of most columnar and transitional epithelium by stratified squamous epithelium, and replacement of corneal epithelium by heavily-keratinized epithelium (vitamin A deficiency)

Replacement of fibrous tissue by calcified bone (many scars, which in the real world may be considered "normal")

Replacement of laryngeal, tracheal, and costal cartilages by bone (old age)

Replacement of normal gastric epithelium with intestinal epithelium in stomach disease ("intestinalization")


Metaplasia


AdaptationIf underlying stimulus is removed, cells can return to

normal.

Hyperplasia cell loss due to apoptosis normal number of cells

Hypertrophy lysosome ingestion of excess cell organelles normal cell size

Atrophy production of additional organelles normal cell size

Metaplasia differentiation back to original cell type


AdaptationIf stimulus persists, pathology results

Cell death

Loss of cell function

Malignant change

The latter is most likely to occur in the setting of metaplasia (of any type) which is often a significant risk factor for the development of carcinoma.

Often preceded by development of pre-invasive neoplastic change = dysplasia.


Summary

Causes of disease Types of injurious agents Hypoxia & Ischaemia Physical agents including Radiation Chemical injury Infectious agents Immune / Genetic / Nutritional

Mechanisms of cellular adaption Consequences

cellular pathology prof orla sheils causes of disease adaptive responses 2nd year pathology 2011

Documents

year pathology

basis of pathology

hypoxia v ischaemia

hypoxia neurons

form of hypoxia

cell injury exogenous

types of cell injury

cell injury reversible